Division of Dockets Management (HFA-305),
Food and Drug Administration,
5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852.

Docket ID: FDA-2015-N-5017
"Banned Devices; Proposal to Ban Powdered Surgeon's Gloves, Powdered Patient Examination Gloves, and Absorbable Powder for Lubricating a Surgeon's Glove."
Agency: Food and Drug Administration (FDA)
Parent Agency: Department of Health and Human Services (HHS

To whom it may concern:

The International Adhesions Society (IAS) provides information, advocacy, support and research for patients and families suffering from adhesions, abnormal fibrous tissue connections caused by surgery or disease such as infection or endometriosis. Established in 1998, the IAS operates mainly through social media and its websites www.adhesions.org and pelvicpainology.com.

In the Supplementary Information to the published proposed rule, the risk of adhesion formation associated with glove powder is cited frequently by FDA as one of the main reasons for the proposed ban. FDA correctly states that various types of glove powder have long been known to provoke adhesions and granulomatous peritonitis.

Adhesions are associated with bowel obstruction, pain and infertility. About one third of patients undergoing abdominal or pelvic surgery will be hospitalized nearly twice in the 10 years after an initial surgical procedure for a problem related to adhesions, or for a procedure that could be complicated by adhesions,1 for example by increased operative time, bladder injury, unintended enterotomy and infection. We have estimated conservatively that the costs of adhesions from in-patient admissions alone could be between $6 and $12 billion annually in the USA, equivalent to 20%-40% of the entire budget of the US National Institutes of Health (NIH). Patients with abdomino-pelvic adhesions often progress to experience overlapping and coalescing urinary, bowel, genital and musculoskeletal symptoms similar to those experienced by patients with other pelvic pain-related conditions in a condition we have termed CAPPS (Complex Abdomino-Pelvic and Pain Syndrome).2

Given that adhesions are a significant medical and economic problem we welcome the proposal by FDA to ban powdered gloves and absorbable powder as a positive step in the quest to improve surgical outcomes, particularly by reducing adhesion formation.

We are concerned that this proposal is far too late in coming and lags behind actions taken in Germany in 1998 and the UK in 2008. A ban was considered in 1997 which would have, in a phased manner required “manufacturers to convert to powder-free production or provide safety data, including foreign body and airborne allergen concerns, by a certain date.” FDA elected not to pursue this approach on the grounds that:
“(1) A ban would not address exposure to natural latex allergens from medical gloves with high levels of natural latex proteins; (2) a ban of powdered gloves might compromise the availability of high quality medical gloves; and (3) a ban of powdered gloves might greatly increase annual costs by almost as much as $64 million over the alternative approach proposed by FDA in the “Draft Guidance for Industry and FDA Staff: Medical Glove Guidance Manual.”

It is unclear as to whether these additional $64 million of costs would have been borne by manufacturers or the consumers of gloves. The costs of lower abdominal, in-patient adhesiolysis in 1988 were estimated at $1.18 billion and published in 19933. Ignoring the fact that this figure does not include other costs related to adhesions, $64 million represents less than 6% of the cost of adhesions. Whilst there are many factors that contribute to adhesions, it is not unreasonable to assume that glove powder may have contributed a modest 6% to the costs associated with adhesions. Accordingly the savings of $64 million of glove costs would likely have been more than compensated for by a reduction in adhesions-related costs. These costs have certainly been borne by patients, payors and the taxpayer.

Given that “at least 93 percent of medical providers have switched to non-powdered gloves” the ban may at this point be largely academic and does nothing to help the millions of patients who may, literally, carry forever the scars (adhesions) of their exposure to glove powder that occurred since 1997 until today.

We welcome however FDA’s interest in adhesions reflected by the current proposal and urge FDA to take other steps to address the problems of adhesions:

1. We request that FDA clarify its position regarding the requirements for endpoints used in clinical trials conducted to support approval of adhesion barrier devices.

In 2000, an IAS presentation was one of several made to a combined panel advising the General and Plastic Surgery Devices, and the Obstetrics and Gynecologic Devices divisions on what became the “Guidance for Resorbable Adhesion Barrier Devices for Use in Abdominal and / or Pelvic Surgery,”4 issued in 2002. A central part of the discussion was the endpoint requirements used in clinical trials conducted to support approval of adhesion barrier devices. In three prior advisory panel meetings that considered the approval of adhesion barriers (Sepracoat, Seprafilm and Intergel), FDA had raised the question as to whether endpoints consisting of clinical outcomes such as pain, bowel obstruction or infertility, should be required for approval of the device. It was argued by IAS, as well as by industry and medical experts, that the endpoints of the incidence, extent and nature of adhesions used historically were clinically relevant in and of themselves. Further, although clinical outcome endpoints would be desirable, it would be unduly burdensome and costly for companies to obtain these endpoints. These arguments were accepted by the panel and this is reflected in the issued guidance document.

We have since learned through informal discussions with companies who are developing adhesion barrier products, that in private meetings, FDA have insisted that “incidence, extent and quality” endpoints would be insufficient for approval, and that “clinical outcome” endpoints would be required. This is contrary to the statements made in the guidance document given the spectre of cost has resulted in the cancellation of the development programs for adhesion barrier products by a number of companies. Since the only three products currently approved in the USA for pelvic or abdominal adhesions are limited in various ways, FDA’s apparently unwritten policy leaves current and future adhesions patients bereft of any hope that adhesion formation or reformation can be prevented effectively.

In the absence of this unclear policy, other companies have attempted to introduce “adhesion barrier” products by exploiting the fact that FDA allows them to claim that their Class II devices intended typically for tissue reinforcement may “minimize tissue attachments.” Such claims are supported mainly by preclinical data and certainly not by the sort of clinical safety and efficacy data the guidance document describes for adhesion barriers. How a “tissue attachment” and a “tissue adhesion” differ is unclear. Indeed one company marketing such a device uses the term “attachments” in its marketing materials intended for US use and “adhesions” in otherwise identical materials distributed elsewhere. This situation has lead to the off-label use of these devices as adhesion barriers. There is a literature report (from Canada) of delayed absorption of the device and foreign body and giant cell reaction to such a material used as an adhesion barrier in myomectomy.5 There are other reports of the same material being used in the USA in gynecological surgery as an adhesion barrier which resulted in a tissue reaction6 and migration through the vaginal wall7 which in one case lacerated the woman’s partner.8

Accordingly, this situation has lead on the one hand to the discouragement of the development of true adhesion barriers which demonstrate safety and efficacy and the encouragement of “attachment barriers” which are clearly being used as adhesion barriers with adverse safety consequences. Neither of these scenarios is good for the patient and we request that FDA clarifies publicly its policy on this matter.

2. We request that FDA initiates a screening and awareness program for patients at long term risk of effects of Intergel.

Intergel was a ferric crosslinked hyaluronic acid adhesion prevention solution that was approved in 2002 after a dispute resolution panel, only to be withdrawn in 2003 after reports of deaths, delayed onset fever, infection and tissue reactions in what has been termed “possible Intergel Reaction Syndrome.”9 The early toxicity of Intergel is believed to be mainly due to iron.10 Iron accumulation is known to be involved in participation in redox reactions leading to tissue damage and inflammation; joint, heart and liver disease; diabetes, cancer and Alzheimer’s disease.11,12 The single dose of iron given to patients in the form of Intergel may accelerate this accumulation and patients at most risk of iron accumulation may be those with a genetic predisposition (homo - or heterozygotes for hereditary hemochromatosis), ethnic propensity (Irish/Scottish origin), prior hysterectomy or male gender. We estimate that 25-50% of Intergel-exposed patients may fall into one or more of the high risk categories for iron accumulation.

There were approximately 50,000 US patients exposed to Intergel and approximately another 30,000 patients elsewhere. Registries for adhesion barriers have been advocated13
On behalf of these many thousands of patients at risk of early development of a condition related to iron overload, we request that FDA implements screening and awareness program for Intergel patients to be vigilant for the effects of iron overload and to be able to intervene early.

3. We request that FDA resolves rapidly the issues in the citizen petition relating to Seprafilm.

We note a petition was filed on July 7 2015 by Public Citizen which requested that Seprafilm® Adhesion Barrier be removed from the market because “it has not been shown to be safe and effective and has been associated with death and severe injury.”14 We are concerned about the allegations made in this petition as well as the apparent unethical lapses related to the unlawful promotion of Seprafilm which lead to fines of $55 million being levied against Genzyme.15,16

A full consideration of these allegations is beyond the scope of this document. While it appears to us that some of the charges are without foundation, others require further investigation and the analysis of data that is not in the public domain.

We are most concerned that this matter be resolved quickly and publicly. Allowing the matter to linger will add to the uncertainty caused by FDA’s unclear policy on clinical trial endpoints (above) and have an even more detrimental effect on the willingness of companies to invest in adhesion barrier development.

We have estimated conservatively that the costs of abdomino-pelvic adhesions from in-patient admissions alone are between $6 and $12 billion annually in the USA, equivalent to 20%-40% of the entire budget of the US National Institutes of Health (NIH). Various estimates suggest that between 50 and 90% of patients undergoing surgery will form adhesions.

Aside from the human and medical burden of adhesions, the enormous economic burden of adhesions should be enough to motivate FDA to do whatever is in its power to alleviate this serious problem. We welcome FDA’s proposal to deal with what is now one small aspect of the problem, but request that FDA takes further steps to help current and future adhesions patients by:
• Clarifying its policy on endpoints to be used in clinical studies for adhesion barrier approval
• Implementing a screening and awareness program for patients exposed to Intergel to be vigilant for the effects of iron overload and to be able to intervene early.
• Resolving rapidly the issues raised by the citizen petition concerning Seprafilm.
• Finding other ways to fast track the approval of adhesion barriers and to encourage investment in this field.

/s/ signed by email submission

David Wiseman Ph.D., M.R.Pharm.S.
Founder, International Adhesions Society (IAS), www.adhesions.org
President, Synechion, Inc., www.synechion.com
President, KevMed, LLC., www.kevmed.com

Background and Disclosure of Conflicts
The IAS is funded mainly by its owner Synechion, Inc. (www.synechion.com), a research and consulting company specializing in the science and business of adhesions. The IAS is not a “not-for-profit” organization. Founded in 1998 and presided over by this author, Synechion’s work is based on an expertise in the field dating back to 1987 and involvement in a large majority of the anti-adhesion products on the market or in development.

The IAS has made a number of achievements including the founding of the world's first clinic for the integrated diagnosis and treatment of adhesions, the characterization of the problems of ARD and CAPPS and the identification of PainShield® MD, a portable wearable therapeutic ultrasound device as a novel and effective analgesic treatment option for patients suffering from pelvic pain and related painful disorders. Accordingly, this author founded KevMed, LLC to market PainShield MD. Although Synechion, Inc. consults for a number of companies with commercial interests in this subject, this submission has not been solicited by other commercial entities.

Reference List

1. Ellis H, Moran BJ, Thompson JN, et al. Adhesion-related hospital readmissions after abdominal and pelvic surgery: a retrospective cohort study. Lancet. 1999;353:1476-1480.
2. Wiseman DM. Disorders of adhesions or adhesion-related disorder: monolithic entities or part of something bigger--CAPPS? Semin Reprod Med. 2008;26:356-68.
3. Ray NF, Larsen JW Jr, Stillman RJ, Jacobs RJ. Economic impact of hospitalizations for lower abdominal adhesiolysis in the United States in 1988. Surg Gynecol Obstet. 1993;176:271-6.
4. Food and Drug Administration. Guidance for resorbable adhesion barrier devices for use in abdominal and/or pelvic surgery; guidance for industry. 2002.
5. Sheizaf B, Tulandi T. Unabsorbed intraabdominal polylactide adhesion barrier. J Minim Invasive Gynecol. 2011;18:10-1.
6. Food and Drug Administration. MAUDE Adverse Event Report: MAST BIOSURGERY SURGIWRAP SURGICAL MESH. February 1, 2010; accessed June 17, 2016. Web Page. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/Detail.CFM?MDRFOI__ID=1674854.
7. Food and Drug Administration. MAUDE Adverse Event Report: MAST BIOSURGERY SURGIWRAP SURGIWRAP, 130X200X0.02MM. December 18, 2009; accessed June 17, 2016. Web Page. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/Detail.CFM?MDRFOI__ID=1652399.
8. Food and Drug Administration. MAUDE Adverse Event Report: SURGIWRAP. November 7, 2006; accessed June 17, 2016. Web Page. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/Detail.CFM?MDRFOI__ID=1379626%20.
9. Wiseman DM. Possible Intergel Reaction Syndrome (pIRS). Ann Surg. 2006;244:630-2.
10. Wiseman D. Possible Intergel Reaction Syndrome (pIRS): mechanisms and general consequences for patients undergoing surgery. J Minim Invasive Gynecol. 2006;13:S67.
11. Tishler TA, Raven EP, Lu PH, Altshuler LL, Bartzokis G. Premenopausal hysterectomy is associated with increased brain ferritin iron. Neurobiol Aging. 2012;33:1950-8.
12. Bartzokis G, Tishler TA, Lu PH, et al. Brain ferritin iron may influence age- and gender-related risks of neurodegeneration. Neurobiol Aging. 2007;28:414-23.
13. Wiseman DM. Registries for anti-adhesion products? Fertil Steril. 2006;86:771; author reply 771-2.
14. Sorscher, S and Carome, M. Citizen Petition to withdraw approval of Seprafilm Bioresorbable Membrane (P950034) and initiate a mandatory recall. July 7, 2015; accessed May 11, 2016. Web Page. Available at: http://www.citizen.org/documents/2266.pdf.
15. US Department of Justice. Genzyme Corporation to pay $32.5 million to resolve criminal liability relating to Seprafilm. Sanofi subsidiary admits unlawful conduct and agrees to enhance its compliance program. March, 2015; accessed May 23, 2016. Web Page. Available at: https://www.justice.gov/opa/pr/genzyme-corporation-pay-325-million-resolve-criminal-liability-relating-seprafilm.
16. US Department of Justice. Genzyme Corp. to pay $22.28 million to resolve false claims allegations related to “slurry” used in patients. December 20, 2013; accessed May 23, 2016. Web Page. Available at: https://www.justice.gov/opa/pr/genzyme-corp-pay-2228-million-resolve-false-claims-allegations-related-slurry-used-patients.